One of the presentations that caught our attention was one by Dr. Mark Zimmerman, Professor of Psychiatry and Human Behavior at Brown University and the Director of the Adult Outpatient and Partial Hospital Division at Rhode Island Hospital.

Dr. Zimmerman asked the question; just how generalizable are depression treatment studies to the clinical population? And how has this changed over the past 20 years?

He conducted a study on more than 1200 patients with a primary diagnosis of major depressive disorder and subjected them to semi-structured interviews in which he applied the inclusion and exclusion criteria of just over 120 placebo-controlled antidepressant efficacy trials.

The results of this study generated concerns that perhaps the issue of generalizability is bigger than we thought, certainly, clinicians were the most oblivious to this.

In this interview we will learn the implications of this study in detail, examine its impact on our clinical practice and hear Dr. Zimmerman’s views on how to approach a patient who isn’t responding to multiple medication trials.

Dr. Rashad: The first question is “What can you tell us about the general efficacy of antidepressants?”

Dr. Zimmerman: Antidepressants are effective. While not every study finds that medication is more effective or efficacy is superior to placebo, half of placebo-controlled trials find that active antidepressant medications separate from placebo. So, medication works. The question is not whether antidepressants work but, “who do they work for?”

Dr. Rashad: Could you share with us findings from antidepressant effectiveness trials?

Dr. Zimmerman: Well, there are some large trials perhaps best illustrated by STAR*D that looked at patients on various medications. There was no placebo group in STAR*D and looked at the effectiveness of treatment for depression in real world clinical practice. Patients get better but perhaps not as well as we had thought or had hoped they would get. If you keep doing trials, if I recall correctly, after three treatment efforts, 68% or about 2/3 of the patients will achieve at least briefly remission status. It doesn’t necessarily mean sustained remission but will achieve remission status. So, most patients will get significantly better for some period of time whether or not that was due to the passage of time, whether or not that was due to the interaction between patient and clinician, whether or not it’s due to taking some pill and the expectation of getting better or the so-called non-specific effects of treatment, whether or not it was due to changes in the person’s life. So stressors that were contributing to the depression in the first time have either resolved or reversed themselves. We don’t know. That’s why it’s necessary to do placebo-controlled trials. But most patients did get better.

Dr. Rashad: How easy is it to apply the results of antidepressant efficacy trials into clinical practice?

Dr. Zimmerman: The problem, the major problem with efficacy trials is that the criteria used to select patients are so restrictive that the vast majority of patients in clinical practice wouldn’t make it in to a trial. Thus, we really don’t know whether or not medications are better than placebo for the vast majority of patients seen in our real world clinical practice. One implication of that is that a number of patients are being overtreated with medication which means that they’re being exposed unnecessarily to some side effects. Unfortunately, we just don’t know which patients it is. If I knew that a patient was going to respond to placebo, I’ll prescribe placebo because the side effect burden is a lot less. I just don’t know who my placebo responders are. That’s the problem we have in clinical practice.

Dr. Rashad: So basically, efficacy trials have narrowed their scope when recruiting patients with depression. How else have things changed?

Dr. Zimmerman: Over the past two decades, new medications have been approved for the treatment of depression and they have new mechanisms of action. So, while there are new mechanisms of action which allow us to continue to prescribe for longer periods of time and continue to engender hope in our patients and continue to allow the placebo effect, the passage of time, the patient-doctor interaction, the therapeutic interaction that occurs, the brief psychotherapy that occurs, all of those things are going along with prescribing new medications or alternatives which I think have a therapeutic benefit.

Dr. Rashad: How do you think narrowing the scope has impacted the way clinicians interpret the evidence from such trials?

Dr. Zimmerman: Clinicians really don’t pay much attention to how such studies are done. Clinicians really don’t pay much attention to the fact that the patient that they’re seeing in their office or I should say the vast majority – And when I say vast majority, I’m talking 80%, 85%, 90% of the patients. But the vast majority of the patients that they see in their practice would not make it in to an efficacy trial and therefore, we do not know whether their improvement, if they improve, is truly due to the active ingredient of the medication or due to as I’ve mentioned before the non-specific effects of treatment.

Dr. Rashad: So, I find it, as a practitioner, quite disturbing the 90% number that you gave. That 90% of my patients wouldn’t be included in the clinical trial. What can a clinician, in your opinion, do about that?

Dr. Zimmerman: So, I know the patient would not make it in to a trial. Does that mean I don’t prescribe? I think it does have an influence on my clinical practice but it’s a little bit more subtle than the decision to prescribe or not to prescribe. And I have seen patients come to me who have said “I’ve been on everything.” And they’re right. They have been on everything. They have through the years been on every approved antidepressant, certainly every new generation approved antidepressant plus combinations. Well before that, I’m having discussions with my patients after let’s say two or three or four failed trials and perhaps a failed course of either transcranial magnetic stimulation or ECT about let’s not keep beating this dead horse. Let’s not keep looking for the magic pill.

First of all, many of these patients, if not almost all of these patients, have comorbid disorders. And I’m talking to them more from a psychotherapeutic perspective and saying let’s figure out how you’re going to manage your symptoms. Let’s take a chronic disease approach towards treatment, a disease management approach towards treatment rather than an antibiotic curative approach. That type of disease management or chronic disease management approach for individuals who have failed a few trials actually is very therapeutic.

Dr. Rashad: The aspect you would say is the most significant, is the mindset aspect, correct?

Dr. Zimmerman: That’s exactly right. Yes. It has an effect on how I approach patients because one of the elements of the placebo response is positive expectation. And if a patient comes to me who has failed four different medications or combinations, I don’t want to say or convey to them your case is hopeless. What I do want to convey to them is I think we can help you but you’re going to have to do some work. And we can work together and let’s talk about what’s been going on. And such individuals usually have so much psychosocial stuff going on in their lives. As part of our Partial Hospital Program, we routinely bring in family members because an individual’s psychiatric illness occurs in a family context.

Dr. Rashad: Have you found that for different reasons we, as psychiatrists, are sometimes falling in to a reductionistic approach focused on just prescribing medications, hoping to find that magical antibiotic cure?

Dr. Zimmerman: Well, in part, we’re incentivized to do so. So at least in this country, reimbursement is greater for seeing four 15-minute med checks in an hour rather than two 1/2-hour visits or one 45-minute to an hour visit. So there’s a financial incentive to focus on prescribing. And you go to conferences like this one and other conferences as well where the focus is – and you read not just our journals but the throwaway publications about new medication options and there’s a focus on prescribing, prescribing, prescribing. If the person isn’t responding, well then you should augment and then try a different augmentation strategy. That’s what the focus has been on. And quite frankly, it’s a lot easier to do a medication treatment trial than it is to do a psychotherapy treatment trial. They’re a lot more difficult to do. So as a result, our research literature is inundated with pharmacotherapy treatment trials rather than a balance of pharmacotherapy and psychotherapy treatment and augmentation trials.

Dr. Rashad: How would you summarize all that we have spoken about to our listeners?

Dr. Zimmerman: So I would say in summary as clinicians, we need to be humble in our knowledge of how efficacious our biological therapies are. And when I say humble in how efficacious they are, it’s not necessarily to imply that they’re not efficacious. It may well be as much a problem with our diagnostic approach in that we continue to live in a world that lacks biomarkers to identify our subtype individuals with the heterogeneous diagnosis of major depressive disorder. So we need to recognize that major depressive disorder is a heterogeneous condition. It’s reached through many different pathways. One of which is biogenetic. And as a result, as a consequence of that, our pharmacotherapy interventions appear both efficacious but limited in efficacy. And we need to broaden our scope in terms of how to approach the treatment of individuals and not just focus on biology and prescribing but understand the full person, understand the context in which their symptoms are occurring, understand the context in which their symptoms are not only occurring but affecting other individuals.

Key Points:

There is good evidence to suggest that antidepressants are effective. After three treatment trials about 2/3 of the patients will achieve, remission status.

Antidepressant efficacy trial criteria have become so restrictive that up to 90% of patients in clinical practice wouldn’t make it into a trial.

We should, however, keep in mind that patients, often have comorbid disorders and significant psychosocial and family issues that may need to be addressed.

The mindset used to approach patients who may be deemed as ‘treatment resistant’ is of importance, instilling a “disease management approach” rather than an antibiotic curative approach may very well prove to be effective.

The following people participated in this episode: Dr. Flavio Guzman as the general editor, Andy Rhode as the audio engineer, Pamela Gonzalez as the project manager and myself Dr. Wegdan Rashad as the host and of course, Dr. Mark Zimmerman for joining us today podcast.

Thank you for joining us in today’s podcast until the next episode, good bye!

References:

Zimmerman, M., et al. Have treatment studies of depression become even less generalizable? A review of the inclusion and exclusion criteria in placebo-controlled antidepressant efficacy trials published. Mayo Clinic Proc 2015; 90: 1180–6.

Zimmerman, M. The FDA’s failure to address the lack of generalisability of antidepressant efficacy trials in product labelling. The British Journal of Psychiatry (2016) 208, 512–514.